Molecular dynamics simulation of amorphous indomethacin

Area of Science:

• Computational chemistry and materials science.
• Investigating amorphous solid-state properties of pharmaceuticals.

Background:

• Amorphous indomethacin (IMC) is a metastable material whose physical stability is critical for pharmaceutical applications.
• Understanding the dynamic and structural properties of amorphous IMC is essential for predicting its long-term stability.

Purpose of the Study:

• To investigate the dynamic and structural properties of amorphous indomethacin using molecular dynamics (MD) simulations.
• To predict the physical stability of amorphous IMC by analyzing its molecular behavior.

Main Methods:

• MD simulations of 105 indomethacin (IMC) molecules and 12 water molecules.
• Model construction using X-ray diffraction data and Amber-ff03 force fields.
• Simulations performed at various temperatures (600 K, 400 K, 298 K) to capture glass transition and solid-state behavior.

Main Results:

• Simulated amorphous IMC density (1.312 g/cm³) closely matched experimental values (1.32 g/cm³).
• Estimated glass transition temperature (Tg) was 384 K, higher than the experimental 320 K due to rapid cooling.
• Complex hydrogen-bonding patterns and conformational dynamics were observed in amorphous IMC, differing from crystalline forms.
• A novel method for calculating diffusion coefficients in non-Einsteinian systems was developed.
• Simulated water diffusion coefficient in IMC glass (2.7 × 10⁻⁹ cm²/s) aligned well with experimental data (0.9–2.0 × 10⁻⁹ cm²/s).

Conclusions:

• MD simulations provide valuable insights into the structural and dynamic properties governing the physical stability of amorphous IMC.
• The study successfully predicted water diffusion in amorphous IMC, linking it to sub-Tg relaxation processes.
• The developed analytical method enhances the study of molecular diffusion in complex amorphous systems.